RheumNow Podcast - The Bad News That's Fit to Print (8.21.20) Save

It's the 08/21/2020. This is the RheumNow podcast. Hi. I'm doctor Jack Cush, executive editor of rheumnow.com. In this edition, a real downer edition, oh my.

It's about delays, discontinuations, and setbacks. All is bad news and none of it has to do with COVID. Imagine that. We'll start off with some COVID reports from Canada. Actually, bunch of dermatologists in one of the dermatology journals looked at their 2,000 patients who are on biologics, a sizable group.

They're taking IL-seventeen inhibitors, TNF inhibitors, IL-twelve twenty three inhibitors, 23 by themselves. They wanted to see what happened during the pandemic with regard to use. In their study, they found that only one point one percent of their two thousand patients stopped their biologic. Surprising. As you know, a lot of our patients didn't have a lot of guidance about what to do.

Although the guidance that was out there said, don't stop your medicines until you talk to your doctor or unless you're hospitalized, but nonetheless, very few of their patients stopped. The interesting thing was of the few that did stop, there was a reasonable rate of flares. For instance, five of the twenty three who stopped and had to restart their biologic because of flares, and that's flares of their skin disease. So, I think it's good news that our patients didn't stop their biologic during this era. I think it's an important message that we need to perpetuate, in our, arthritis patients as well.

So, we do know that diabetes is a serious comorbidity and risk factor for worse outcomes in patients with the coronavirus. And there's a preprint that has recently appeared, I think it's going to get a lot of press, I think it's very important. It's a retrospective review. Again, here come all the caveats that limit the studies we have thus far on COVID. This one's a preprint, it's a retrospective review, it's an EHR, a medical record study, but it's an EHR review of over 25,000 COVID patients tested within the University of Alabama Birmingham Healthcare System.

And they showed that the COVID patients who were taking metformin had a significantly lower mortality risk, compared to COVID patients who had diabetes and weren't taking metformin. It was, again, an odds ratio of point three three. That's a sixty seven percent reduction in mortality. If true, that's amazing data. What else looks good in COVID?

Well, there's another preprint analysis of RCTs and non RCTs over 11 studies looking at JAK inhibitor use in patients with COVID showing it too reduced mortality and also very significant, like a ninety eight percent reduction and also reduced ICU admission significantly over ninety percent. Another analysis in that same publication looked at type one interferon therapy, not a lot of experience there, but it also has significant reductions in mortality. Again, are these preprints? Is this selective reporting? Is this reality?

But the good news is there's some good news. Similarly, another study comes out of a New Jersey hospital system study of seven sixty four patients who went on to, receive tocilizumab in about twenty seven percent of those patients. Turns out that again, tocilizumab, when used, had a lower death rate, forty nine percent, versus sixty one percent for those who didn't take tocilizumab. That's a risk reduction of about one third. And they saw similar results with regard to tocilizumab preventing the use of mechanical ventilation or progression to mechanical ventilation.

So, tocilizumab, the story in COVID seems to be mostly positive, a few negatives, but mostly positive at this point. Again, as I said last week, we're waiting for the full reports, the well designed studies, double blind, randomized, placebo controlled trials. They're going to start streaming in in September and October. BMJ Open reports on the rate of dis rate of referral amongst RA patients. I looked this one up.

In fact, this is a year old report coming from The, United Kingdom and the National Health Service, and they showed that there was a significant median delay from first symptom of rheumatoid arthritis to seeing a rheumatologist. Their median number was twenty seven weeks. This sort of supported, supports my idea that, and my belief, that there still is a significant delay in patients being referred. You know, we've been preaching, you know, early referral, early referral, early referral. But how many of you rheumatologists have actually written a note to any or all of your colleagues saying, send me your rheumatoid, I have a facilitated spot for them.

No. You kinda take what comes your way. We don't advertise for the patients we wanna see. If you ran an RA only clinic as opposed to you'll see anything clinic, don't you think you would be doing that? Meaning, telling people, send me your RA patients, and let's get it done.

Of that twenty seven week delay, it turns out that at least five weeks of that was due to patient delay. We know that patients are significant factor in not wanting to seek help even though they have a need for help. GP delays is almost seven weeks of that number, hospital delays almost five weeks. So, you start adding it up, you get to at least a six month delay in the average patient with rheumatoid arthritis before they can see a rheumatologist. We really still need to work on that.

Arthritis research and therapy reports on a very interesting study on, lupus and discontinuation or, stopping hydroxychloroquine. This comes from three New York City lupus clinics, where they have some big lupus clinics in New York City, and they specifically looked at patients who were, older with lupus, who stopped their hydroxychloroquine. The average age in this clinic, in this cohort of 58 patients was 60 years of age. They had lupus for more than twenty years. They had been on Plaquenil for an average of thirteen plus years.

And the reasons for discontinuing hydroxychloroquine was almost half of them, or forty two percent with retinal toxicity concerns. Patient preference in about a third, adverse effects in fifteen percent. Turns out that there was no difference in flare rates in lupus patients who stopped their hydroxychloroquine and a matched population who continued their hydroxychloroquine. So I I know you would think there would be more more flares for a drug that's often, very beneficial, but maybe there's a point in which stopping hydroxychloroquine can be stopped without risk. And these people, it was for retinal toxicity or adverse events.

But again, most of the flares that were seen, and we're talking about either nineteen or sixteen percent flare rates, so fairly low number, were mainly flares as far as musculoskeletal complaints and skin. So really quite manageable, and maybe reassuring for older patients who have to stop their hydroxychloroquine. So an interesting article this week came out in one of the GI journals about the risk of developing inflammatory bowel disease. The study comes from the Karolinska Institute, which looked at twenty four thousand new incident cases of either Crohn's or ulcerative colitis. Compare them one to five match controls.

So that's a twenty four thousand versus almost a hundred twenty thousand. And they looked at the use of antibiotics in that system. Turns out antibiotic use was associated with near a near doubling of the risk of developing inflammatory bowel disease. The adjusted odds ratio being one point eight eight. So this has been hinted at in several of our diseases as well.

Does antibiotics increase the odds? Can antibiotics, especially repeated use of antibiotics? And in their study, they showed that people who received three or more, antibiotic courses were more likely than that number I just quoted to develop IBD. Not a lot more likely, but certainly more likely. But does that alter one's microbiome?

And does that change one's biology and flip it to the biology you don't want, that might lead to developing inflammatory disease like inflammatory bowel disease. It's provocative, information. The J Rheum has an interesting study about the benefits of biologics in preventing cardiovascular events. This comes from a fairly large cohort, almost nineteen thousand RA patients in a FORWARD study, eighteen hundred of whom developed, had a cardiovascular event, during this ten year follow-up, I believe it was. They found that the risk reduction for cardiovascular event was seen with methotrexate.

We've known that from Fred Wolf, and Choi published almost twenty years ago. Methotrexate dropped the risk of cardiovascular events by, in their study here, eighteen percent, hazard ratio is zero point eight two. Above and beyond that, you can do better for people who are taking TNF inhibitors, and or abetacept. TNF inhibitor use dropped, the the rate by again eighteen percent and abetacept by fifty percent compared to patients who are just taking, DMARDs alone. So this goes to data we talked about before that chronic use of a biologic, often with methotrexate, is what gives you the cardiovascular benefit.

It's not short term use, it's gotta be the long term use, sometimes as long as three years or more, or at least two years or more, twenty seven months is what I remember from some old studies we covered at, EULAR a few years ago, that said that you then get the benefit of cardiovascular risk reduction. A single center prospective study of 50 severe lupus patients, thirty one years for those who were treated with, mycophenolate, 28 years old for those treated with IV cytotoxin. Specifically in this study, this prospective study, they looked at ovarian dysfunction to see what would happen and whether or not the use of either of those drugs would lead to premature ovarian failure. In their follow-up, these patients, they it did not. Neither drug led to premature ovarian ovarian failure.

Now the sample size is relatively small, but nonetheless, I think it's encouraging data. Ovarian dysfunction was, certainly present for the first several months. One is on IV but it was subclinical, didn't amount to much. And the measure of ovarian function hormone levels and whatnot sort of reverted to normal, I think was after six months or a year in patients treated with IV cytotoxin. This is somewhat encouraging data.

Think even, in a situation where we worry about what's going to happen to ovarian function and patients taking these very strong therapies for severe lupus, lupus nephritis, etcetera. I think the big surprise of the week came from the FDA when they handed out a no go decision to filgotinib. Filgotinib, as you know, is, was poised to be the fourth JAK inhibitor to hit the market. Its data looked very, very good from Darwin studies and Finch studies that you may have heard about that we talked about here. The great thing about filgotinib was it was a once a day drug, like some of the other ones we have.

It was a selective JAK1 inhibitor. Maybe that was a good thing. Their safety profile, their their clinical data looked like everybody else's, looked really strong, looked really good. But their safety data may have been a smidge better than even the other JAK inhibitors. Very low numbers of infections, almost like no almost low, low, low, no numbers for cancer, but less events with regard to zoster and with regard to maybe even VTEs, venous thromboembolic events.

Well, poised for a decision that was to be handed out this week, the FDA instead handed out a complete response letter. What does that mean? It means that they're asking for more information before they can make a decision about what to do with filgotinib. Specifically, they want the results of two studies that were commissioned, to study sperm function, sperm numbers. In animal models, preclinical testing, it looked like the higher doses, the doses that might conform to their asking dose of two hundred milligrams a day might be associated with some testicular toxicity, again, in rats and other animals, but it didn't have any clinical consequences in those same animal studies.

So it's really unclear. Nonetheless, the FDA asked for specifically some sperm studies, and that would have led to two different studies. One was called the MANTA study, which is fully enrolled, 250 patients with either, IBD, either UC or Crohn's disease, and they're studying sperm function in patients who are receiving, this filgotinib. There's another study called MANTA RAY where the same sperm studies are being done in our rheumatology patients, RA, PSA, I think, undifferentiated or I'm sorry, non radiographic axial SpA. That study has halted about a 100 patients who've been enrolled and studies on hold, not because of this, but because of the COVID.

Several of their studies that were in process are on hold, and I'm sure they're going to resume. The problem is these studies, the MANTA study is not completed, although it's completed enrollment, its first data analysis won't be until sometime in early twenty twenty one. And it's gonna be even further for the MANTA RAY results. So the FDA is asking for more, data from these sperm studies. They also expressed, concern about the risk benefit, behind the two hundred milligram dose.

The interesting thing with filgotinib is they're asking for FDA approval of one hundred or and two hundred milligrams once a day in, RA patients not responding to or having toxicity to DMARR therapy. Now, just a week or two ago, the EMA CHMP committee which recommends whether a drug should be approved or not by EMA recommended filgotinib one hundred and two hundred milligrams be approved. And a week later, the FDA turns around says, woah, woah, woah, let's look at the sperm data. They also want to look at the two hundred milligram data. Again, what's interesting about that is all the JAK inhibitors that have gone before the FDA have asked for two drugs.

That happened with tofacitinib, they wanted five BID and 10 BID, they only got five BID. That happened with baricitinib they wanted two and four milligrams only got two two milligrams. OOPA didn't even ask they did all studies with fifteen and, thirty milligrams once a day and only upadacitinib fifteen milligrams once a day was approved and they all got the same sort of warnings and whatnot. So, I think it was unlikely that the FDA would be poised to approve a two hundred milligram dose unless it's safer and maybe even more effective than the lower one hundred milligram dose. And I'm not sure they can meet that benchmark.

Anyway, there's no decision at this point, not by the FDA, and it's gonna be until 2021, could even be 2022 before that actually goes further. So what about, other JAK inhibitors? Upadacitinib, you know, has been around now for a while, we're looking at this. Their trials are still being rolled out. Specifically, the SELECT early trial was reported this week.

It's a head to head trial in patients with about a half a year of rheumatoid arthritis who either are treated with methotrexate or with upadacitinib fifteen or thirty milligrams. The primary endpoint in this study was DASRA CR DASCRP remission or an ACR 50. At twenty four weeks, upadacitinib fifteen and thirty milligrams was significantly better than methotrexate alone with an ACR 50 of either 52 to 56 for the JAK inhibitor or 28%, more or less double the response for methotrexate. Similarly, the ACR 20 responses were higher with OOPA, seventy eight or seventy nine percent with OOPA and fifty eight percent with methotrexate. So, no new safety signals in here.

Again, JAK inhibitors have looked very good in head to head studies against methotrexate, and this is particularly in early RA. You may remember from, EULAR, we talked about this study, but a select, cut of this study looking at patients who were treated even earlier and yes, their response rates were even higher. I think that's really somewhat, exciting. Lastly, there's a report from, I think it was JAMA, that looked at lupus anticoagulant activity in COVID. We've talked about that before, you know, COVID patients are at higher risk for thrombotic events and some bleeding events.

It's been associated with high D dimer levels and evidence of antiphospholipid antibodies and lupus anticoagulant, activity. The question is, is that related to inflammation or is that really part of the disease? In this particular study of one hundred and eighty seven COVID patients who underwent lupus anticoagulant testing, they showed when, the COVID patients were lupus anticoagulant, let me see, negative, the, let's see, the rate of COVID was twenty two percent. When they were lupus anticoagulant positive, the rate of COVID was forty four percent. More importantly, if you were, lupus anticoagulant positive and you had COVID positivity and disease, you had a sixty four percent chance of documented thrombosis, either arterial or venous.

Again, this suggests a a consistent role for the this lupus anticoagulant and that it may significantly contribute to the thrombotic events that we're seeing in the coronavirus infections. Lastly, I want to, again remind you that our daily email and our website has a new feature on it that is going to be discussed here in the podcast, and it's called Back Talk. Back talk is, a place you can go to, a button you can click on either the email or on the daily website. And there you can record your question, your case, your thing that you want to discuss, something that you didn't like that I said in one of these podcasts, and we will discuss them, maybe yours, maybe someone else's, in future podcasts to come. Look for it.

It's called back talk, where back talk is a good thing. That's it for this week on the podcast. Make sure you go to the website to check out these citations and more. Take care.